Journal of Medical Genetics最新文献

{"title":"Biallelic variants in <i>DNAH10</i> are associated with skeletalf developmental abnormalities and ciliary dysfunction.","authors":"Rui Zheng, Xinrong Du, Jierui Yan, Gelin Huang, Zhuoyao Guo, Wei Li, Hanyun Que, Yuting Wen, Fei Yan, Daijuan Chen, Li Dai, Yu Shi, Weicheng Chen, Wenming Xu","doi":"10.1136/jmg-2025-111109","DOIUrl":"https://doi.org/10.1136/jmg-2025-111109","url":null,"abstract":"<p><strong>Background: </strong>Primary cilia are essential for skeletal development by coordinating key signalling pathways in osteoblasts and chondrocytes. While pathogenic variants in approximately 40 genes have been linked to skeletal ciliopathies, additional causative genes remain to be identified. Although DNAH10 is well characterised in motile cilia, its role in primary cilia remains unclear.</p><p><strong>Methods: </strong>Whole-exome sequencing was performed in two individuals with skeletal developmental abnormalities and identified biallelic <i>DNAH10</i> variants. In vitro assays were used to assess the effects of these variants on DNAH10 protein abundance. <i>Dnah10</i> knockout mice were generated to investigate the associated skeletal phenotypes and underlying mechanisms.</p><p><strong>Results: </strong>Biallelic <i>DNAH10</i> variants were identified in two individuals with skeletal developmental abnormalities. In vitro, these missense variants were associated with reduced DNAH10 protein abundance. <i>Dnah10</i>-deficient mice recapitulated key skeletal features, including polydactyly, impaired cartilage development and abnormal ossification. Mechanistically, <i>Dnah10</i> loss was associated with abnormal primary cilia morphology, attenuated Hedgehog signalling, impaired osteoblast differentiation and defective chondrocyte maturation.</p><p><strong>Conclusion: </strong>Our findings support <i>DNAH10</i> as a candidate gene associated with skeletal developmental abnormalities and ciliary dysfunction and suggest a previously underappreciated role for DNAH10 in primary cilia-related skeletal development beyond its established role in motile cilia.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathogenic mobile element insertion in the <i>MEN1</i> gene mimicking a deletion in MLPA: characterisation by long-read sequencing.","authors":"Aleksandra Pfeifer, Jadwiga Zebracka-Gala, Agnieszka Pawlaczek, Artur Zajkowicz, Agata Abramowicz, Karolina Tecza, Agnieszka Kotecka-Blicharz, Hanna Langer-Maciol, Marta Cieslicka, Dagmara Rusinek, Malgorzata Porc, Renata Cyplinska, Malgorzata Oczko-Wojciechowska","doi":"10.1136/jmg-2025-111230","DOIUrl":"https://doi.org/10.1136/jmg-2025-111230","url":null,"abstract":"<p><strong>Background: </strong>Mobile element insertions (MEIs) disrupting coding sequences are rare but clinically significant mutations that are often missed by standard next-generation sequencing (NGS) workflows. Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant tumour predisposition syndrome caused by pathogenic variants in the <i>MEN1</i> gene.</p><p><strong>Methods: </strong>Patients included in this study were referred for genetic testing of hereditary cancer syndromes. In a validation of our NGS-based copy number variant detection pipeline, four cases showed discrepancies between NGS and multiplex ligation-dependent probe amplification (MLPA) results. Further investigation using soft-clipped read analysis and the MEI detection tool Scramble revealed an Alu insertion in the <i>MEN1</i> gene. Long-read whole genome sequencing (LR-WGS) was used for validation and complete characterisation of the variant. Additionally, 2014 retrospective NGS samples were analysed with Scramble. Relatives of probands were tested with MLPA and PCR. Positive samples were analysed with Sanger sequencing.</p><p><strong>Results: </strong>The apparent exon 2 deletion detected by MLPA was shown to be a false positive caused by an Alu insertion within the probe binding site. LR-WGS confirmed the pathogenic variant (<i>MEN1</i>:c.143_144insAlu) and resolved its complete sequence. Screening of the retrospective cohort revealed no additional MEIs. Altogether, we identified 10 affected individuals from two Polish families carrying hereditary <i>MEN1</i>:c.143_144insAlu, which segregates with MEN1 syndrome.</p><p><strong>Conclusion: </strong>We report a novel pathogenic Alu insertion in the <i>MEN1</i> gene, which is associated with MEN1 syndrome. Our findings underscore the importance of incorporating MEI detection into routine diagnostics. It also emphasises the necessity of interpreting single-exon MLPA deletions cautiously, as recommended in the MLPA protocol.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147774010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Uterine serous carcinoma and germline genetic testing: patterns of referral, completion and pathogenic variant detection.","authors":"Lauren Tostrud, Simge Bagci Turkmen, Jiaqi Zhang, Rachel Hodan, Kerry Kingham, Oliver Dorigo, James M Ford, Allison W Kurian, Talayeh S Ghezelayagh","doi":"10.1136/jmg-2025-111285","DOIUrl":"https://doi.org/10.1136/jmg-2025-111285","url":null,"abstract":"<p><strong>Background: </strong>Current guidelines recommend consideration of germline genetic testing for patients with uterine serous carcinoma (USC) but real-world data are limited on completion rates of testing and pathogenic variant (PV) identification. This study aimed to evaluate the rate of genetic testing referral and completion in a cohort of patients with USC, determine the prevalence of clinically meaningful PVs found on testing and explore factors associated with genetics referral and testing completion.</p><p><strong>Methods: </strong>We retrospectively examined the medical records of all individuals diagnosed with USC between 2019 and 2024 seen at a single academic cancer centre. Outcomes of interest included referral for germline genetic testing, completion of testing and testing results.</p><p><strong>Results: </strong>Of 131 individuals included, 5 (3.8%) had prior genetic testing and only 45 (34.4%) were recommended to undergo genetic testing or referred to cancer genetics. Younger individuals and those with a personal history of cancer other than USC or family history of breast or ovarian cancer were more likely to be referred. Nine (26.5%) of 34 individuals who completed germline testing had a PV identified in a cancer-related gene, including <i>BRCA1</i>, <i>BRCA2</i>, <i>BRIP1</i>, <i>CHEK2</i>, <i>MSH6</i>, <i>PMS2</i> and <i>ATM</i>. Only a personal history of cancer other than USC was independently associated with the discovery of a PV on germline genetic testing. In those without a prior personal history of cancer, the PV prevalence was 5.6%.</p><p><strong>Conclusions: </strong>Given the high prevalence of PVs in this population, germline genetic testing for all patients diagnosed with USC can provide clinically meaningful benefit but is currently underused in practice.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147773070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Best practice recommendations for bioinformatics approaches applied to high-throughput sequencing for rare disease and cancer diagnosis within the UK National Health Service.","authors":"Jamie M Ellingford, Erik Waskiewicz, Ashley J Pritchard, Javier Lopez, Rebecca Morgan, Emily Ley, Matt Lyon, Alona Sosinsky, Dalia Kasperaviciute, Joo Wook Ahn","doi":"10.1136/jmg-2025-111289","DOIUrl":"https://doi.org/10.1136/jmg-2025-111289","url":null,"abstract":"<p><strong>Background: </strong>Establishing best practice recommendations helps to increase consistency, equity and innovation in clinical genomics services. Bioinformatics approaches are a core component of clinical genomics services that use high-throughput genomic sequencing applied in the diagnosis of rare disorders and cancer. While a broad range of international recommendations exist for genomic diagnostic testing and genetic variant classification, the current UK-specific best practice recommendations for bioinformatics approaches applied in this context are outdated.</p><p><strong>Methods: </strong>We assembled a team of bioinformaticians and scientists with diverse expertise in rare disease and cancer genomics applied in clinical diagnostics within the UK National Health Service. Through structured discussion, polls and surveys, we developed an updated set of best practice recommendations for bioinformatics approaches applied to high-throughput genomic sequencing in clinical genomic testing.</p><p><strong>Results: </strong>We provide best practice recommendations across the spectrum of activities within a clinical genomics bioinformatics pipeline, including quality control, primary, secondary and tertiary analysis approaches and shared knowledge bases. We also comment on issues related to software development and maintenance. The recommendations can be applied to multiple sequencing technologies and encompass both targeted and whole genome sequencing approaches applied to germline and tumour DNA samples.</p><p><strong>Conclusion: </strong>The best practice recommendations outlined in this study provide a national framework for adoption and innovation of bioinformatics approaches across diverse clinical genomic testing strategies in the UK National Health Service.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147773943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-read genome sequencing increases diagnostic yield in a short-read sequencing unsolved developmental epileptic encephalopathy (DEE) cohort.","authors":"Chanatjit Cheawsamoot, Rungroj Thangpong, Wanna Chetruengchai, Songphon Kanlayaprasit, Wuttichart Kamolvisit, Phawin Kor-Anantakul, Adjima Assawapitaksakul, Ponghatai Boonsimma, Sathida Poonmaksatit, Krisnachai Chomtho, Tayard Desudchit, Vorasuk Shotelersuk","doi":"10.1136/jmg-2026-111514","DOIUrl":"https://doi.org/10.1136/jmg-2026-111514","url":null,"abstract":"<p><p>Developmental epileptic encephalopathy (DEE) comprises neurodevelopmental disorders with early-onset seizures and developmental impairment. Despite >900 implicated genes, many patients remain undiagnosed after short-read sequencing (SRS). We assessed long-read genome sequencing (LR-GS) in 38 previously unsolved infantile-onset DEE probands (10 singletons, 28 trios). Variant detection included single nucleotide variants (SNVs), structural variants, copy number variants and short tandem repeats in established repeat expansion disease genes. LR-GS identified candidate variants in 8 out of 38 probands (21%) missed by SRS: five large deletions, one SNV in a low-mappability region of <i>NSF</i>, one case resolved via haplotype phasing of compound heterozygous SNVs without parental samples and one case where LR-GS detected an allele missed due to coverage gaps. An additional eight probands (21%) harboured variants technically detectable by SRS but were missed due to newly associated genes, synonymous variants lacking splicing evaluation or prior analytic pipelines. LR-GS substantially increases diagnostic yield in unsolved infantile-onset DEE, supporting its incorporation into clinical workflows as a second-tier genetic test for otherwise unsolved neurodevelopmental disorders.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147773996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"VHL gene fragment analysis: large inversion detection in <i>Alu</i> region for clinical applications.","authors":"Ryan N Baugher, Stephanie D Mellott, Kristen M Pike, Todd B Young, Heidi E Lawhorn, Stephen M Hewitt","doi":"10.1136/jmg-2026-111493","DOIUrl":"https://doi.org/10.1136/jmg-2026-111493","url":null,"abstract":"<p><p>von Hippel-Lindau (VHL) is an autosomal-dominant tumour susceptibility disorder associated with pathogenic germline variants in the <i>VHL</i> gene that put patients at increased risk of developing benign and malignant tumours within various organs. While current CLIA (Clinical Laboratory Improvement Amendments) genetic tests demonstrate a high detection rate of pathogenic <i>VHL</i> variants, clinical manifestations of VHL with atypical germline alteration undetectable by established genetic tests have been reported by Vocke <i>et al</i>, indicating the need for bespoke methods confirming germline alterations. We CLIA-validated a test using PCR and fragment analysis that evaluates a pathogenic inversion of 291 kb found within intron 2 of <i>VHL</i> and the 3' UTR of <i>TTLL</i>3 in patients with canonical VHL manifestations and no conventional germline alterations. Validation results matched as expected by achieving 100% concordance. Although clinical diagnosis of VHL is possible in the absence of conclusive pathogenic cause, this report demonstrates bespoke CLIA methodologies are essential for managing hereditary diseases and promoting early symptom detection. Our CLIA assay allows for greater confidence in diagnosis for families dealing with complex structural germline alterations and may aid in future efforts at corrective therapies to ease patient suffering. This work was performed in our CLIA-certified laboratory (CLIA ID # 21D0947274).</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147773709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rare missense variants in <i>MYO7A</i> and <i>OTOP2</i> genes in a South Korean Meniere's disease cohort.","authors":"Mai T Pham, Pablo Cruz-Granados, Prathamesh T Nadar-Ponniah, Han Chow Chua, Seung Hyun Jang, Heon Yung Gee, Jinsei Jung, Jae Young Choi, Sung Huhn Kim, Jose A Lopez-Escamez","doi":"10.1136/jmg-2025-111426","DOIUrl":"https://doi.org/10.1136/jmg-2025-111426","url":null,"abstract":"<p><strong>Background: </strong>Meniere's disease (MD) is a polygenic condition defined by episodes of vertigo associated with sensorineural hearing loss and tinnitus. Genetic studies in familial MD in East Asian populations are limited, and the potential MD genes remain to be established in non-Finnish European populations.</p><p><strong>Methods: </strong>By exome sequencing and rare variant analysis, we have searched for existing and novel genes associated with MD in a South Korean cohort of 16 MD individuals with bilateral sensorineural hearing loss.</p><p><strong>Results: </strong>We have found one individual with two rare missense variants in the <i>OTOP2</i> gene, a new candidate gene for MD and three heterozygous variants in the <i>MYO7A</i> gene, supporting the hypothesis of biallelic inheritance. Wild-type and mutated protein models were compared, and currents were measured in the human proton channel OTOP2 expressed in <i>Xenopus laevis</i> oocytes to further elucidate functional consequences. Structural changes in the T364M or H435Q OTOP2 variants were not associated with changes in measured currents, regardless of pH or Ca²⁺ concentrations.</p><p><strong>Conclusion: </strong>The <i>OTOP2</i> gene is a novel candidate for the audiovestibular dysfunction observed in MD. Furthermore, rare variants in the <i>MYO7A</i> gene, previously associated with European MD, have been found in the South Korean cohort. The OTOP2 protein was found in the basal cells of the stria vascularis, spiral ganglion neurons and inner hair cells in the organ of Corti, suggesting a dual role in endolymphatic homeostasis and neural signal transmission.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147773970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinically significant DNA variation from the GENCOV and HostSeq COVID-19 genome sequencing studies.","authors":"Erika Frangione, Radhika Mahajan, Juan De Los Rios, Selina Casalino, Navneet Aujla, Saranya Arnoldo, Alexandra Binnie, Bjug Borgundvaag, Marc Dagher, Luke Devine, Hanna Faghfoury, Steven Marc Friedman, Chun Yiu Jordan Fung, Zeeshan Khan, Gregory Morgan, David Richardson, Seth Stern, Ahmed Taher, Jennifer Taher, Jordan Lerner-Ellis","doi":"10.1136/jmg-2025-111029","DOIUrl":"10.1136/jmg-2025-111029","url":null,"abstract":"<p><strong>Background: </strong>Vast amounts of genome sequencing data generated from large-scale research studies like HostSeq provide an opportunity to summarise the spectrum of pathogenic variation in a subset of the Canadian population. Sharing variant-level data with public databases, like ClinVar, is crucial for advancing our understanding of genomic variants related to Mendelian diseases. However, such entries are often incomplete or contain discrepancies which render interpretation and classifications less useful.</p><p><strong>Methods: </strong>The GENCOV and HostSeq cohorts were annotated and summarised using custom workflows to identify variants with a pathogenic and likely pathogenic (P/LP) classification in ClinVar. These variants were further filtered using custom gene panels, gnomAD frequency, variant type, gene-disease relationship and the number of reputable ClinVar laboratory submissions. Manually assessed variants from the GENCOV study were compared with ClinVar classifications to identify discrepancies.</p><p><strong>Results: </strong>A total of 1956 unique variants were manually classified as P/LP through the GENCOV study. Of these, 65% (1276) were also identified in ClinVar, and among those, 69% (889) had concordant P/LP classifications. The manual assessment of unique exonic variants in GENCOV yielded a higher number of putative P/LP variants (1595), including truncating and missense variants compared with the 127 unique exonic P/LP variants in HostSeq.</p><p><strong>Conclusion: </strong>These results highlight that a large proportion of P/LP variation is either absent or has conflicting evidence for pathogenicity in ClinVar, emphasising the importance of periodic reassessment, discrepancy resolution and updates to ensure completeness and accuracy of public databases.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"299-307"},"PeriodicalIF":3.7,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147317429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Frequency of familial hypercholesterolaemia-causing genetic variants in the 100 000 Genomes Project cohort: whole genome sequencing analyses of 77 260 participants.","authors":"Marta Futema, Martin Bird, Ash Haeger, Ellen Pinder, Anthony O'Rourke, Elijah R Behr, Steve E Humphries","doi":"10.1136/jmg-2025-111201","DOIUrl":"10.1136/jmg-2025-111201","url":null,"abstract":"<p><strong>Background: </strong>Heterozygous Familial Hypercholesterolaemia (HeFH) is caused by pathogenic variants in <i>LDLR</i>, <i>APOB</i>, <i>APOE</i> or <i>PCSK9</i>, leading to elevated low-density lipoprotein-cholesterol and increased cardiovascular risk. In the UK, HeFH affects ~1 in 288 individuals. The 100 000 Genomes Project (100KGP) generated whole genome sequencing (WGS) data from >85 000 participants recruited primarily with cancer or rare inherited disorders. We analysed WGS data to assess the prevalence and spectrum of FH-causing variants.</p><p><strong>Methods: </strong>Variants in <i>LDLR</i>, <i>APOB</i>, <i>APOE</i> and <i>PCSK9</i> were extracted from 100KGP WGS data and annotated using expert-reviewed ClinGen curation. Demographic, ancestry and linked health records were incorporated. Analyses were restricted to unrelated individuals.</p><p><strong>Results: </strong>Among 54 818 unrelated participants, 167 were heterozygote for an FH-causing variant, giving a prevalence of 1:328 (95% CI 1:285 to 1:386). Prevalence was similar across ancestries, including African (1:388) and South Asian (1:276). Variant distribution was: <i>LDLR</i> 67%, <i>APOB</i> 26.5%, <i>APOE</i> 3.5% and <i>PCSK9</i> 3%. Two individuals carried two FH variants, consistent with homozygous FH. Among 22 442 genetic relatives, 77 also carried an FH variant. Of all variant carriers, 53% were female, mean age at recruitment was 41.3 years, with 43 younger than 18 years, and 54.3% had documented hypercholesterolaemia.</p><p><strong>Conclusions: </strong>The prevalence and gene distribution of FH-causing variants in 100KGP are consistent with UK estimates. Differences in variant spectrum across ancestries were observed; however, FH prevalence was similar. Participants who consented to the return of actionable findings were informed, providing direct clinical benefit from genomic research.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"284-290"},"PeriodicalIF":3.7,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13151451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146157315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reclassification of variants of uncertain significance in type I collagen genes: a national reference laboratory experience.","authors":"Nurhaziqah Supari, Duncan Baker, Sylvia Keigwin, Sophie Delaney, Seiko Makino, Meena Balasubramanian","doi":"10.1136/jmg-2025-111334","DOIUrl":"10.1136/jmg-2025-111334","url":null,"abstract":"<p><strong>Background: </strong>The availability of large volumes of data from genetic testing has enabled the interpretation of more DNA variants, contributing to a greater number of identified variants of uncertain significance (VUS). The growing number of VUS causes a burden of inconclusive findings in clinical practice. Osteogenesis imperfecta (OI) is a genetically heterogeneous connective tissue disorder causing bone fragility and limb deformity. Pathogenic variants in two collagen genes, <i>COL1A1</i> and <i>COL1A2,</i> account for around 90% of all OI.</p><p><strong>Methods: </strong>Data mining of the variants from Sheffield Diagnostic Genetics Service, the national OI testing hub (UK), was conducted to collate all VUS in <i>COL1A1</i> and <i>COL1A2</i> identified. All VUS were then reclassified according to the latest 2024 ACGS (Association for Clinical Genomic Science) best practice guidelines.</p><p><strong>Results: </strong>A total of 161 VUS in <i>COL1A1</i> and 98 VUS in <i>COL1A2</i> were identified and reanalysed. For <i>COL1A1</i>, we found that 2% VUS were upgraded to likely pathogenic (LP), 23% of the VUS were downgraded to likely benign and benign, 12% were reclassified as hot VUS and the remaining 63% have not changed classification as VUS. With regard to <i>COL1A2</i>, only 1% of the VUS were upgraded to LP, 25% were downgraded to likely benign and benign, 13% were reclassified as hot VUS and 61% remained as VUS.</p><p><strong>Conclusion: </strong>From this study, we demonstrated that iterative reanalysis of VUS is crucial in clinical practice as new data and evidence become available. This dynamic process will significantly improve diagnostic accuracy and inform patient care decisions.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"277-283"},"PeriodicalIF":3.7,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146157259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}